It is estimated that five million people in the United States are afflicted with chronic stable angina resulting from ischemic episodes, many of which are caused by Coronary Artery Disease (CAD) in which one or more of the larger coronary arteries become obstructed or completely blocked by atherosclerotic plaque. Despite medical therapy and mechanical revascularization, for example, via angioplasty or bypass surgery, many patients suffering from CAD could benefit from additional protection against ischemia. One method of providing this additional protection is angiogenesis, or the development of new coronary vessels providing collateral circulation to myocardial tissue in proximity to obstructed arteries.
Experimental and clinical studies have demonstrated a protective role of collateral circulation in hearts having coronary obstructions. Unfortunately, the ‘natural’ process by which angiogenesis occurs may not be adequate to reverse ischemia in most CAD patients. But, there are several pieces of evidence indicating that it is possible to promote angiogenesis for the alleviation of myocardial ischemia. There are several conceptually and practically different approaches for angiogenic therapy.
A genetic approach, in which angiogenic growth factors, such as basic fibroblast growth factor, are administered (as proteins or as genes, with systemic or local direct myocardial delivery) is still under clinical investigation, has been shown to be of limited efficacy, and is burdened with the potential dangers of aberrant angiogenesis in non-targeted adjacent, or even remote, tissues, such as vulnerable atherosclerotic plaques, occult neoplasms, or diabetic retinopathy. Another approach involves the transfer of autologous stem cells to the ischemic region, producing a localized, effective angiogenetic response in the ischemic region.
A non-genetic approach to angiogenic therapy develops natural therapeutic strategies, potentiating them through physical and pharmacological stimuli. Three classes of stimuli have been proposed to promote coronary angiogenesis: exercise, adenosine-modulating drugs, and heparin. Each of these three, when used alone, do not seem to trigger clinically relevant angiogenesis that translates into improved exercise tolerance for CAD patients. Apparently, however, heparin and dipyridamole (an adenosine-modulating drug) critically potentiate exercise-induced angiogenesis and adenosine critically potentiates heparin-induced angiogenesis.